Alzheimer's disease (AD) already is a serious public health problem and looms as a potential public health disaster as coming generations achieve longer average life spans. Numerous experiments and epidemiologic studies point to products of cyclooxygenase (COX) and lipid peroxidation as potential contributors to processes that initiate AD. Of the many potential products generated by these pathways, we have shown that both brain prostaglandin [unreadable]2 (PGE2), a product of COX, and p2-isoprostanes (IsoPs), products of lipid peroxidation, are elevated early hi the course of AD; both compounds activate eicosanoid receptors, thus establishing them as potential therapeutic targets. The long-range goals of this project are to determine the mechanisms by which PGE2 and F2-IsoPs contribute to the neuronal oxidative damage that is characteristic of AD. We will test the hypothesis that activation of specific PGE2 receptor subtypes in brain can enhance or suppress neuronal oxidative damage, and that specific F2-IsoPs enter into a reinforcing cycle by further stimulating production of PGE2 via activation of cell surface receptors. The specific aims are: (1) to determine the PGE2 receptor subtypes that enhance or suppress cerebral oxidative damage in vivo using a mouse model of AD pathogenesis, (2) to determine the specific PGE2 receptor subtypes that enhance or suppress Ap42- activated migroglial-mediated oxidative damage and neurodegeneration, (3) to determine receptor-mediated mechanisms by which F2-IsoPs stimulate PGE2 production in neurons and glia, and thereby reinforce the processes investigated in Specific Aims 1 and 2. Successful completion of these experiments will further pur knowledge of the mechanisms that underlie neurodegeneration and identify novel therapeutic targets to suppress oxidativedamage to brain in AD and perhaps other neurodegenerative diseases.